TY - JOUR
T1 - Safety, tolerability, and anti-fibrotic efficacy of the CBP/β-catenin inhibitor PRI-724 in patients with hepatitis C and B virus-induced liver cirrhosis
T2 - An investigator-initiated, open-label, non-randomised, multicentre, phase 1/2a study
AU - Kimura, Kiminori
AU - Kanto, Tatsuya
AU - Shimoda, Shinji
AU - Harada, Kenichi
AU - Kimura, Masamichi
AU - Nishikawa, Koji
AU - Imamura, Jun
AU - Ogawa, Eiichi
AU - Saio, Masanao
AU - Ikura, Yoshihiro
AU - Okusaka, Takuji
AU - Inoue, Kazuaki
AU - Ishikawa, Tetsuya
AU - Ieiri, Ichiro
AU - Kishimoto, Junji
AU - Todaka, Koji
AU - Kamisawa, Terumi
N1 - Funding Information:
KK was the coordinating principal investigator and led the clinical conduct at the Komagome Hospital, TK was the principal investigator at Kohnodai Hospital, SS was the principal investigator at Kyushu University Hospital. JI, MK and KN were study sub-investigators at Komagome Hospital, and EO at Kyushu University Hospital. KK consider concept of clinical trial, acquired funding, interpret the clinical data and wrote an original draft. TK, SS, EO, II, JK, KT, and TK collected, analysed, and interpreted the data. TK, SS, and EO review and edit the manuscript. MK, KN, and JI investigated and interpreted clinical data. KH, MS, and YI analysed and interpreted the histological data. TO, KI, and TI interpreted the clinical data and organised the safety of the study. JK led the work for the statistical analysis. II contributed to PK analysis. All authors read and approved the final version of the manuscript. We would like to acknowledge Akemi Ikoma, Kozue Kobayashi, and Maiko Nishihara for their help in patient recruitment. We would like to thank all of the research and clinical staff at Tokyo Metropolitan Komagome Hospital, especially Yasuo Azuma, Noriyo Okamoto, and Naoko Horikawa for their hard work and valuable contribution to the study. In addition, we would like to thank the clinical staff at Kyushu University Hospital; Kayo Toyosaki, Tsutomu Ymaguchi, Saori Imada and Yushi Kashihara. This investigator-initiated study was supported by a grant “Development the Translational Research Network Program (JP20lm0203057h0003)” from the Japan Agency for Medical Research and Development (AMED). None of the funders played any role in the study design or data analysis and interpretation. We thank Editage ( www.editage.jp) for English language editing. Anonymised data presented in the manuscript or acquired during the course of the clinical trial will be made available upon request to the corresponding author following the publication of the article. The data will be made available in a form that does not deviate from what is accepted by local regulatory authorities with respect to the handling of patient data and that is adherent with the policies of the Tokyo Metropolitan Komagome Hospital.
Funding Information:
This investigator-initiated study was supported by a grant “Development the Translational Research Network Program (JP20lm0203057h0003)” from the Japan Agency for Medical Research and Development (AMED). None of the funders played any role in the study design or data analysis and interpretation. We thank Editage ( www.editage.jp ) for English language editing.
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/6
Y1 - 2022/6
N2 - Background: We conducted an exploratory study to assess the safety tolerability, and anti-fibrotic effects of PRI-724, a CBP/β-catenin inhibitor, in patients with hepatitis C virus (HCV)- and hepatitis B virus (HBV)-induced cirrhosis. Methods: This multicentre, open-label, non-randomised, non-placebo-controlled phase 1/2a trial was conducted at three hospitals in Japan. Between July 27, 2018, and July 13, 2021, we enrolled patients with HCV- and HBV-induced cirrhosis classified as Child–Pugh (CP) class A or B. In phase 1, 15 patients received intravenous infusions of PRI-724 at escalating doses of 140, 280, and 380 mg/m2/4 h twice weekly for 12 weeks. In phase 2a, 12 patients received the recommended PRI-724 dose. The primary endpoints of phases 1 and 2a were the frequency and severity of adverse events and efficacy in treating cirrhosis based on liver biopsy. This study was registered at ClinicalTrials.gov (no. NCT 03620474). Findings: Three patients from phase 1 who received the recommended PRI-724 dose were evaluated to obtain efficacy and safety data in phase 2a. Serious adverse events occurred in three patients, one of which was possibly related to PRI-724. The most common adverse events were diarrhoea and nausea. PRI-724 did not decrease hepatic fibrosis with any statistical significance, either by ordinal scoring or measurement of collagen proportionate area at 12 weeks; however, we observed statistically significant improvements in liver stiffness, Model for End-stage Liver Disease score, and serum albumin level. Interpretation: Intravenous administration of 280 mg/m2/4 h PRI-724 over 12 weeks was preliminarily assessed to be well tolerated; however, further evaluation of anti-fibrotic effects in patients with cirrhosis is warranted.
AB - Background: We conducted an exploratory study to assess the safety tolerability, and anti-fibrotic effects of PRI-724, a CBP/β-catenin inhibitor, in patients with hepatitis C virus (HCV)- and hepatitis B virus (HBV)-induced cirrhosis. Methods: This multicentre, open-label, non-randomised, non-placebo-controlled phase 1/2a trial was conducted at three hospitals in Japan. Between July 27, 2018, and July 13, 2021, we enrolled patients with HCV- and HBV-induced cirrhosis classified as Child–Pugh (CP) class A or B. In phase 1, 15 patients received intravenous infusions of PRI-724 at escalating doses of 140, 280, and 380 mg/m2/4 h twice weekly for 12 weeks. In phase 2a, 12 patients received the recommended PRI-724 dose. The primary endpoints of phases 1 and 2a were the frequency and severity of adverse events and efficacy in treating cirrhosis based on liver biopsy. This study was registered at ClinicalTrials.gov (no. NCT 03620474). Findings: Three patients from phase 1 who received the recommended PRI-724 dose were evaluated to obtain efficacy and safety data in phase 2a. Serious adverse events occurred in three patients, one of which was possibly related to PRI-724. The most common adverse events were diarrhoea and nausea. PRI-724 did not decrease hepatic fibrosis with any statistical significance, either by ordinal scoring or measurement of collagen proportionate area at 12 weeks; however, we observed statistically significant improvements in liver stiffness, Model for End-stage Liver Disease score, and serum albumin level. Interpretation: Intravenous administration of 280 mg/m2/4 h PRI-724 over 12 weeks was preliminarily assessed to be well tolerated; however, further evaluation of anti-fibrotic effects in patients with cirrhosis is warranted.
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U2 - 10.1016/j.ebiom.2022.104069
DO - 10.1016/j.ebiom.2022.104069
M3 - Article
C2 - 35605429
AN - SCOPUS:85130807003
SN - 2352-3964
VL - 80
JO - EBioMedicine
JF - EBioMedicine
M1 - 104069
ER -
